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B·R·A·H·M·S™ CgA II KRYPTOR™ is an automated immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE™) technology for quantitative determination of Chromogranin A concentration in human serum.

B·R·A·H·M·S™ CgA II KRYPTOR™ is to be used in conjunction with other clinical methods as an aid in monitoring of disease progression during the course of disease and treatment in patients with gastroentero-pancreatic neuroendocrine tumors (GEP-NETs, grade 1 and grade 2).

The B-R-A-H-M-S CgA II KRYPTOR assay is based on the formation of a complex comprised of a Chromogranin A (CgA) analyte "sandwiched" between two monoclonal mouse anti-CgA antibodies. One of the antibodies (537/H2) is directed at the epitope AA124–144 and labelled with DiSMP cryptate, the other antibody (541/E2) binds to AA280-301 and is labelled with Alexa Fluor®647.

The measurement principle is based on a non-radiative energy transfer from a donor (cryptate) to an acceptor (Alexa Fluor™647) when they are part of an immunocomplex (TRACE technology (Time-Resolved Amplified Cryptate Emission)).

The fluorescent signal is proportional to the concentration of the analyte to be measured.

With this principle B-R-A-H-M-S CgA II KRYPTOR is a homogenous one-step immunoassay for the quantification of CgA II in human serum. The linear direct measuring range of the assay is from 20-3,000 ng/mL, going up to 1,000,000 ng/mL with automated dilution. Results can be retrieved after a 29 min incubation time.

Here's an analysis of the acceptance criteria and study findings for the B.R.A.H.M.S CgA II KRYPTOR device, based on the provided FDA 510(k) summary:

Acceptance Criteria and Reported Device Performance

Note: The provided document primarily describes analytical performance criteria and clinical performance measures (sensitivity, specificity) rather than explicit "acceptance criteria" in a pass/fail format for clinical decision-making. However, the sensitivity and specificity values obtained from the clinical study serve as the reported device performance against which implicit clinical acceptance would be judged. The analytical performance metrics are generally presented as numerical results meeting industry standards (CLSI guidelines).

Study Details:

1. Sample size used for the test set and the data provenance:

   • Clinical Study (for Sensitivity and Specificity): 153 adult GEP-NET patients (grade 1 and 2), with 459 total observations (likely reflecting multiple monitoring visits per patient). The study was described as a prospective study.
   • Clinical Cut-off Derivation: 102 patients with diagnosed well-differentiated G1 and G2 GEP-NETs. This was a retrospective, bicentric observational pilot study.
   • Reference Range Determination: 206 samples from self-declared healthy individuals. Data provenance is USA.
   • Analytical studies: Various sample sizes were used, often involving replicates of pooled or individual human serum samples. For example, LoQ used 420 total replicates from 7 different pools of human serum samples.
   • Provenance for analytical samples: Not explicitly stated but generally implied to be from human subjects, for instance, "human serum samples".

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience):

   • For the clinical study, tumor progression was classified by RECIST 1.1 criteria. This implies that experts (typically radiologists or oncologists) were involved in interpreting imaging (CT/MRI) according to these established criteria to determine the ground truth for tumor progression.
   • The document does not specify the direct number of experts or their specific qualifications (e.g., "radiologist with 10 years of experience"). However, RECIST 1.1 is an internationally recognized standard for evaluating cancer treatment response based on imaging, implying adjudication by qualified personnel.

3. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

   • The ground truth for tumor progression in the clinical studies was established using RECIST 1.1 criteria based on standard imaging (CT/MRI).
   • The document does not explicitly state an adjudication method like "2+1" or "3+1" for discordant interpretations if multiple readers were involved in RECIST assessment. However, RECIST guidelines themselves are designed to standardize interpretation, and clinical trials often employ independent central review or consensus panels for definitive RECIST ratings, though this specific detail is not provided here.

4. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

   • No, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) for quantitative determination of Chromogranin A concentration in human serum, intended to be used in conjunction with other clinical methods as an aid in monitoring. It is not an AI-assisted imaging device or a device that directly aids human readers in interpreting images.

5. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

   • This is an IVD assay, which functions as a "standalone" measurement of a biomarker in serum. The results are generated by the automated instrument (B.R.A.H.M.S KRYPTOR compact PLUS analyzer) without direct human interpretation of the measurement itself. However, the device's output (CgA concentration) is explicitly stated to not be used for standalone diagnosis or monitoring but "in conjunction with other clinical methods." So while the analytical measurement is standalone, the clinical interpretation for decision-making is not.

6. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

   • For the clinical performance evaluation (sensitivity and specificity for tumor progression), the ground truth was imaging-based tumor assessment using RECIST 1.1 criteria. This is a form of expert assessment based on a standardized methodology, often relying on radiologists and oncologists to interpret imaging studies.

7. The sample size for the training set:

   • This document describes an IVD device submission, not a machine learning/AI device. Therefore, the concept of a "training set" for an algorithm in the typical AI sense does not directly apply. The development and validation of the assay itself would have involved numerous samples for optimization and establishment of analytical performance characteristics, but these are not referred to as a "training set" here.

8. How the ground truth for the training set was established:

   • As addressed above, the concept of a "training set" in the context of machine learning/AI is largely inapplicable here. The development of the assay's analytical characteristics (e.g., linearity, precision, detection limits) would be established through standard laboratory practices and reference materials, for which "ground truth" is defined by known concentrations or established analytical methods.

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The B-R-A-H-M-S PCT sensitive KRYPTOR® is an immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE) technology to determine the concentration of PCT (procalcitonin) in human serum and EDTA or heparin plasma.
The B-R-A-H-M-S PCT sensitive KRYPTOR® is intended to be performed on the B·R·A·H·M·S KRYPTOR® analyzer family.
Used in conjunction with other laboratory findings and clinical assessments, B·R·A·H·M·S PCT sensitive KRYPTOR® is intended for use as follows:

• to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock,
• to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission,
• to aid in decision making on antibiotic therapy, for inpatients or patients in the emergency department with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD),
• to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

The B·R·A·H·M·S KRYPTOR® compact PLUS analyzer is a fully automated system. The B-R-A-H-M-S KRYPTOR® compact PLUS analyzer is a closed system and can only operate utilizing special reagents provided by B.R.A.H.M.S GmbH.
The B·R·A·H·M·S PCT sensitive KRYPTOR® is a homogeneous sandwich immunoassay for detection of PCT in human serum or plasma. The measuring principle is based on Time-Resolved Amplified Cryptate Emission (TRACE®) technology, which measures the signal that is emitted from an immunocomplex with time delay.

The provided text describes a 510(k) premarket notification for the B·R·A·H·M·S PCT sensitive KRYPTOR® device, which measures procalcitonin levels. The submission seeks clearance for expanded indications for use based on comparisons to predicate devices and meta-analyses of clinical studies.

Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a tabular format with corresponding performance results for each expanded indication in a single place. Instead, it details various analytical and clinical performance characteristics from previous submissions (DEN150009 and K070310) and new meta-analyses to support the expanded claims.

However, we can infer acceptance criteria from the context of a 510(k) submission, which generally requires demonstrating substantial equivalence to a legally marketed predicate device. This often involves showing comparable analytical performance and equivalent safety and effectiveness for the intended use. For the expanded indications, the performance is demonstrated through meta-analyses of existing clinical trial data.

Inferred "Acceptance Criteria" (based on regulatory expectations for an IVD and expanded claims) and Reported Device Performance:

• %CV values for repeatability ranged from 0.58% to 12.31%.
• Total Reproducibility %CV ranged from 2.57% to 14.88%.

(The table provides detailed SD and %CV for various components like repeatability, between-operator, between-day, between-calibration, between-run, and between-lot for 12 different samples (P10-P16, QC1, QC2, HG1-HG3) with N=56 for most samples and N=54 for HG3.) |
| Linearity/Assay Reportable Range | From DEN150009 (Page 16):

• Direct measuring range: 0.02 µg/L - 50 µg/L
• Measuring range with automatic dilution: 0.02 µg/mL - 5000 µg/L |
  | Detection Limit (LoB, LoD, LoQ) | From DEN150009 (Page 17):
• LoB and LoD determined (same as predicate).
• LOQ (lowest reported concentration level with bias ≤ 5%, % CV ≤ 15%, TE ≤ 30%) = 0.075 µg/L.
• TE ≤ 20% at 0.25 µg/L (bias ≤ 5%, precision CV ≤ 10%)
• TE ≤ 30% at 0.10 µg/L (bias ≤ 5%, precision CV ≤ 15%)
  Performance at key cutoffs (table on Page 17):
• 0.10 µg/L: %CV 10.33, %BIAS 2.07, %TE 19.11
• 0.23 µg/L: %CV 5.04, %BIAS 1.85, %TE 10.17
• 0.27 µg/L: %CV 6.71, %BIAS 0.76, %TE 11.83 |
  | Analytical Specificity/Interference | From DEN150009; supplementary interference studies performed for lower cut-offs (Page 17-18):
• No interference up to specified concentrations for numerous endogenous substances (e.g., Hemoglobin 500 mg/dL, Triglycerides 22.5 mg/mL, Bilirubin 20mg/dL), cross-reacting substances (e.g., Human calcitonin 3.9 ng/mL), and drugs (e.g., Cefotaxim 90 mg/dL, Heparin 8000 IU/L, common asthma/COPD drugs like Budesonide, Albuterol, etc.). |
  | Method Comparison (vs. Predicate) | Qualitative Agreement with VIDAS B·R·A·H·M·S PCT (PCT) on 203 samples (Page 19):
• At 0.10 µg/L: Positive Agreement 86.5%, Negative Agreement 86.8%, Overall Agreement 86.7%, Kappa 0.7309.
• At 0.25 µg/L: Positive Agreement 96.4%, Negative Agreement 98.0%, Overall Agreement 97.5%, Kappa 0.9380.
• At 0.50 µg/L: Positive Agreement 95.6%, Negative Agreement 100.0%, Overall Agreement 99.0%, Kappa 0.9710.
• At 2.00 µg/L: Positive Agreement 79.2%, Negative Agreement 100.0%, Overall Agreement 97.5%, Kappa 0.8702. |
  | Clinical Performance (supporting expanded claims via Meta-analyses) |
  | Aid in decision-making on antibiotic therapy for LRTI (reduce antibiotic use without negative outcomes) | Patient-level meta-analysis (13 RCTs, N=3142 total patients) for LRTI (Page 21):
• 19.2% reduction in relative antibiotic initiation.
• 38% reduction in overall antibiotic exposure (inpatients).
• 51% reduction in overall antibiotic exposure (ED/outpatients).
• 2.9 day reduction in antibiotic duration.
• 3.6 day reduction in total antibiotic exposure.
• No negative effects in regards to mortality, complications, or length of stay.
  Summary table (Page 21):
• Antibiotic initiation: 88.4% (standard) vs. 71.4% (PCT guided)
• Duration of antibiotics: 10 days (standard) vs. 7 days (PCT guided)
• Total exposure of antibiotics: 9 days (standard) vs. 5 days (PCT guided)
• 30-day mortality: 7.4% (standard) vs. 6.7% (PCT guided)
• Complications: 21.1% (standard) vs. 18.0% (PCT guided) |
  | Aid in decision-making on antibiotic discontinuation for sepsis (reduce antibiotic use without negative outcomes) | Patient-level meta-analysis for Sepsis (5 RCTs, N=598 sepsis patients) (Page 22):
• 1.5 day reduction in antibiotic duration.
• 3.2 day reduction in total antibiotic exposure.
• 23% reduction in overall antibiotic exposure.
• No negative effects in regards to mortality, hospital length of stay, or ICU length of stay.
  Summary table (Page 22):
• Total exposure of antibiotics: 12 days (standard) vs. 8 days (PCT guided)
• 30-day mortality: 23.8% (standard) vs. 19.9% (PCT guided) |

2. Sample Size Used for the Test Set and Data Provenance

• Analytical Performance Test Set (Method Comparison):

  • Sample Size: 203 frozen banked samples.
  • Data Provenance: Retrospective. Samples were from the "ProRESP trial bank of consecutive patients with clinically suspected COPD, acute bronchitis and CAP," analyzed for concordance with a predicate device.
  • Country of Origin: Not explicitly stated but the publication referenced, "Schuetz P, et al. Clin Biochem. 2010," suggests European origin (Switzerland is common for Müller and Schuetz research groups).

• Clinical Performance Test Set (Meta-analyses for expanded indications):

  • LRTI Antibiotic Decision Making:
    • Study-level Meta-analysis: 11 Randomized Controlled Trials (RCTs), 4090 patients.
    • Patient-level Meta-analysis: 13 RCTs, 3142 patients.
    • Data Provenance: Retrospective, aggregated from previously published RCTs.
    • Country of Origin: Not specified, but given the list of publications, these would be multi-national clinical trials.
  • Sepsis Antibiotic Discontinuation:
    • Study-level Meta-analysis: 10 RCTs, 3489 patients.
    • Patient-level Meta-analysis: 5 RCTs, 598 patients (after excluding non-sepsis patients).
    • Data Provenance: Retrospective, aggregated from previously published RCTs.
    • Country of Origin: Not specified, but likely multi-national.

3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications

• Analytical Performance (Method Comparison): The "ground truth" here is the measurement by the predicate device (VIDAS B·R·A·H·M·S PCT). No human experts were involved in establishing the ground truth for this direct measurement comparison.

• Clinical Performance (Meta-analyses): For PCT-guided therapy trials, the ground truth for patient outcomes (e.g., diagnosis of LRTI, sepsis, mortality, complications, length of stay, antibiotic duration) would have been established by the clinical teams and investigators involved in each of the original RCTs. The document does not specify the number or qualifications of these individual experts for the initial studies, as it relies on published, peer-reviewed clinical trial data as its basis. The meta-analyses themselves are statistical syntheses of these existing ground truths.

4. Adjudication Method for the Test Set

• Analytical Performance: Not applicable for a quantitative assay method comparison. Results are compared directly between two devices.

• Clinical Performance: For the individual RCTs that form the basis of the meta-analyses, adjudication methods for clinical endpoints would have been defined in their original protocols. The meta-analyses themselves don't involve a separate adjudication process beyond the data synthesis. The text states "Each meta-analysis used random-effects models and calculated point estimates, differences, odds ratios (OR), interquartile ranges (IQRs) and 95% confidence intervals as appropriate," which describes the statistical method, not human adjudication.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

This is an In Vitro Diagnostic (IVD) device (a blood test for procalcitonin), not an imaging AI device. Therefore, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study, which is typically relevant for evaluating medical imaging interpretation (human readers with/without AI assistance), was not conducted. The "comparative effectiveness" demonstrated here is about the utility of the PCT biomarker (measured by the device) in guiding clinical decisions (like antibiotic therapy) when compared to standard care, based on clinical trial outcomes.

6. Standalone Performance

The device is an in vitro diagnostic (IVD) that provides a quantitative measurement of PCT. Its "standalone performance" is implicitly covered by the analytical performance studies (precision, linearity, detection limit, interference). It's not an "algorithm only" device in the sense of an AI interpreting medical images; it's a lab instrument that measures an analyte. Its performance is the accurate measurement of PCT levels.

The "standalone" statement regarding its clinical use (Page 6) is a warning/precaution: "B·R·A·H·M·S PCT sensitive KRYPTOR® is not indicated to be used as a stand-alone diagnostic assay and should be used in conjunction with clinical signs and symptoms of infection and other diagnostic evidence." This clarifies that the clinical decision-making should not solely rely on PCT even if the device itself accurately measures PCT.

7. Type of Ground Truth Used

• Analytical Performance: The ground truth for the method comparison was the quantitative result provided by a legally marketed predicate device (VIDAS B·R·A·H·M·S PCT).
• Clinical Performance: The ground truth for the expanded indications was based on outcomes data and clinical diagnoses established in prospective, randomized controlled trials. These outcomes include antibiotic initiation and duration, total antibiotic exposure, 30-day mortality, complications, and length of hospital/ICU stay.

8. Sample Size for the Training Set

The document does not directly mention a "training set" in the context of machine learning or AI algorithm development, as this is an IVD device measuring a biomarker. The analytical performance data (precision, linearity, detection limits, interference) are part of its fundamental characterization, not typically referred to as a "training set."

For the meta-analyses, the "training" analogous to that for an AI would be the collective body of clinical evidence from the published RCTs. The data from various studies (Ns provided in point 2) are "pooled" or combined within the meta-analysis framework. It's not a single "training set" for a new algorithm, but rather a synthesis of existing clinical evidence to support a new clinical claim for an established diagnostic test.

9. How the Ground Truth for the Training Set Was Established

Since there isn't a "training set" for a machine-learning algorithm in this context, the question translates to: How were the original clinical trial data (which underpin the meta-analyses) established?

The clinical data used in the meta-analyses (serving as the "evidence base" for the expanded indications) were derived from multi-center, prospective, randomized controlled clinical trials (RCTs). In these trials, patient outcomes (e.g., diagnosis, mortality, antibiotic use) were carefully collected and documented by the individual study investigators according to their original study protocols. This type of data from well-designed RCTs is considered high-quality evidence in medical research. The meta-analyses then systematically combined and statistically analyzed the results from these individual studies, effectively using their established "ground truths."

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The B·R·A·H·M·S PCT sensitive KRYPTOR is an immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE) technology to determine the concentration of PCT (procalcitonin) in human serum and EDTA or heparin plasma.

The B.R.A.H.M.S.PCT sensitive KRYPTOR is intended to be performed on the B·R·A·H·M·S KRYPTOR analyzer family.

The B R A H M S PCT sensitive KRYPTOR is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of Intensive Care Unit (ICU) admission for progression to severe sepsis and septic shock.

The B·R·A·M·S PCT sensitive KRYPTOR is also intended for use to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of allcause mortality in conjunction with other laboratory findings and clinical assessments for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission.

Procalcitonin (PCT) is a biomarker associated with the inflammatory response to bacterial infection that aids in the risk assessment of critically ill patients on their first day of Intensive Care Unit (ICU) admission for progression to severe sepsis and septic shock. The percent change in PCT level over time also aids in the prediction of cumulative 28-day mortality in patients with severe sepsis and septic shock.

PCT level on the first day of ICU admission above 2.0 µg/L is associated with a higher risk for progression to severe sepsis and/or septic shock than a PCT level below 0.5 ug/L.

A PCT level that declines ≤ 80% from the day that severe sepsis or septic shock was clinically diagnosed (Day 0) to four days after clinical diagnosis (Day 4) is associated with higher cumulative 28-day risk of all-cause mortality than a decline > 80%.

The combination of the PCT level (≤ 2.0 ug/L or > 2.0 µg/L) at initial diagnosis of severe sepsis or septic shock with the patient's clinical course and the change in PCT level over time until Day 4 provides important additional information about the mortality risk.

The PCT level on Day 1 (the day after severe sepsis or septic shock is first clinically diagnosed) can be used to calculate the percent change in PCT level at Day 4 if the Day 0 measurement is unavailable.

The B·R·A·H·M·S PCT sensitive KRYPTOR is an immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE) technology to determine the concentration of PCT (procalcitonin) in human serum and EDTA or heparin plasma. It contains reagents including Cryptate Conjugate, XL665 Conjugate, and Diluent. Additional required materials include Calibrator, Controls, and KRYPTOR Consumables (Solutions 1, 2, 3, 4, BUFFER, Reaction plates, Dilution plates). The assay is a homogeneous sandwich immunoassay performed on the B·R·A·H·M·S KRYPTOR compact PLUS analyzer, a fully automated system. The measuring principle is based on Time-Resolved Amplified Cryptate Emission (TRACE®) technology, which measures the signal emitted from an immunocomplex with time delay. The system is a closed system and can only operate utilizing specially made reagent kits from B.R. A. H. M.S. The B.R.A.H-M-S KRYPTOR compact PLUS analyzer user interface displays the significant processes within the system to the user. An on-line 'Change in Procalcitonin Calculator' is also available as a web-based software application to aid in the interpretation of results.

B.R.A.H.M.S PCT sensitive KRYPTOR Device Performance Summary

This document describes the acceptance criteria and the supporting study for the B.R.A.H.M.S PCT sensitive KRYPTOR device, which aids in assessing the cumulative 28-day risk of all-cause mortality in patients with severe sepsis or septic shock.

1. Acceptance Criteria and Reported Device Performance

The device's performance regarding prognostic accuracy for 28-day all-cause mortality is evaluated based on the change in PCT levels over time. The primary acceptance criteria for the clinical claim are based on the association between the percent change in PCT level and 28-day all-cause mortality risk.

Table 1: Acceptance Criteria and Reported Device Performance for 28-Day Mortality Risk

Note: The table above primarily focuses on the clinical claim of assessing 28-day mortality risk. Other analytical performance characteristics were evaluated against established CLSI guidelines, which implicitly define acceptance criteria for precision, linearity, stability, etc.

2. Sample Size and Data Provenance for the Test Set

The clinical study (MOSES study - ClinicalTrials.gov Identifier: NCT01523717) evaluated the device's performance.

• Test Set Sample Size: The analysis population for the clinical study consisted of 598 subjects.
• Data Provenance: The data was collected from a prospective clinical trial across 13 investigational sites in the US.

3. Number of Experts and Qualifications for Ground Truth Establishment (Test Set)

The ground truth for the clinical study was 28-day all-cause mortality. This is an objective outcome, and therefore, no human experts were required to establish the ground truth for the test set.

4. Adjudication Method (Test Set)

Given that the primary ground truth for the clinical study was 28-day all-cause mortality, which is a definitive clinical outcome, no adjudication method was necessary for the test set.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No MRMC comparative effectiveness study was mentioned in the provided text. The device is an in vitro diagnostic assay, and the study focused on the performance of the assay itself in predicting mortality, rather than assessing human reader improvement with or without AI assistance.

6. Standalone (Algorithm Only) Performance

The clinical study evaluated the performance of the B.R.A.H.M.S PCT sensitive KRYPTOR assay in assessing 28-day mortality risk. This is inherently a standalone (algorithm only) performance evaluation, as it measures the quantitative change in PCT levels and correlates it with an outcome, without direct human intervention in the measurement interpretation for the purpose of the study's primary endpoint. The Change in Procalcitonin Calculator is a web-based tool provided as an aid for interpretation, but the assay results themselves are generated by the automated instrument.

7. Type of Ground Truth Used

The ground truth used for the clinical study was outcomes data, specifically cumulative 28-day all-cause mortality. This is a definitive patient outcome.

8. Sample Size for the Training Set

The provided document does not specify a separate training set sample size for the clinical study used to validate the mortality risk claim. The study (MOSES study) is described as a "prospective clinical trial... of 858 adult patients," with an "analysis population of 598 subjects." It is an observational study that evaluated the association between PCT change and mortality, rather than training an algorithm on a specific dataset. Therefore, the clinical claim was validated on the 598 subjects from the MOSES study, which may be considered the validation or test set rather than a training set for an AI model. For the analytical performance characteristics (precision, linearity, etc.), specific sample sizes were used for each analytical study, as detailed in section L.1.

9. How the Ground Truth for the Training Set Was Established

As mentioned in point 8, the document does not describe a separate training set for an algorithm that predicts mortality. The clinical study was an observational study that validated the prognostic utility of PCT changes. The ground truth for the outcomes measured in this study (28-day all-cause mortality) was established through patient follow-up and recorded vital status (i.e., objective outcomes data).

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